Background:Postpartumbreastcancers,definedasbreastcancersdiagnosedwithin5-10yearsoflast childbirth,aremorethantwiceaslikelytobecomemetastaticandresultindeath.Thisdevastatingdiagnosis affectsthousandsofyoungwomenannually.Ourpreviousresearchrevealedthatnon-invasivebreasttumor cellsbecomeinvasiveandmetastaticinpostpartummicecomparedtocontrolsinnulliparousmice.Wealso revealedanovelfeedbackloopinvolvingcollagenmediatedupregulationofCOX-2,whichmediatesinvasion andmetastasisinpostpartummice.Subsequentgeneexpressionanalysisrevealedasignificantandspecific upregulationofSEMA7AmRNAinpostpartumbreasttumorcells.TheSEMA7Ageneencodesforsemaphorin 7a(Sema7a),asignalingmoleculethatdrivesneuraldevelopment,immunity,andtissueremodelinginthe lung.OurpreliminarydatademonstratethatsilencingofSEMA7Acelllinederivedpostpartumbreastcancer xenograftsdelaysgrowth,progressiontoinvasivecancer,andreduceslymphangiogenesisinthetumor microenvironment.Inaddition,wehaveanalyzedouryoungwomen?sbreastcancercohorttorevealthat SEMA7Aproteinissignificantlyincreasedinpostpartumpatienttumorsandinnulliparouspatienttumorsthat subsequentlyrecurred.Thus,wepostulatethatSEMA7Aisalsoageneralmediatorofbreasttumor progression.Insupportofthis,ourgeneexpressionanalysisofmultiplehumanbreastcancerdatasetsreveals thatSEMA7AmRNAexpressionisassociatedwithearlyrecurrence,metastasis,anddeath.Cumulatively, thesedatasupportthehypothesisthatSEMA7Apromotestumorprogressioninbreastcancerpatientsand maybeanimportanttherapeutictarget.Objective/Hypothesis:Acollagen-mediatedCOX-2/SEMA7A signalingaxisiskeyforinvasion,stromalremodeling,andinductionofvascularremodelinginthe tumormicroenvironment,allofwhichultimatelydrivemetastasis.SpecificAims:(1)Determinehow collagenleadstoupregulationofCOX-2andSEMA7AandwhethertargetingCOX-2incombinationwith silencingofSEMA7Awillblocktumorcellinvasion.(2)DefinethemechanismsbywhichSEMA7Apromotes vascularremodelingandmetastasis,determinewhethertargetingorco-targetingofSEMA7AandCOX-2will blockmetastasis,anddefinetherelationshipbetweenSEMA7AandCOX-2inpostpartumbreasttumors. Cancerrelevance:Toestablishclinicalrelevance,wewillexaminetherelationshipbetweenSEMA7Aand COX-2proteinexpression,alongwithcollagenandthevasculature,usingmulti-colorimmunostainingand correlatewithinvasionandrecurrenceinourpostpartumbreastcancerpatienttissues.Theexpected outcomesareidentificationofmechanismsbywhichCOX-2andSEMA7Asupportbreasttumorprogression. Suchresultscouldpositivelyimpactthousandsofbreastcancerpatientsbydefiningnewtherapiestargetedat theSEMA7Apathway.GiventhatSEMA7Aexpressionisgenerallylowinadulttissuesdirecttargetingof SEMA7Acouldhavelowtoxicity.